Submissions for variant NM_000527.5(LDLR):c.1049G>A (p.Arg350Gln)

gnomAD frequency: 0.00002  dbSNP: rs875989914

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000850045	SCV004022404	uncertain significance	Hypercholesterolemia, familial, 1	2023-04-28	reviewed by expert panel	curation	NM_000527.5(LDLR):c.1049G>A (p.Arg350Gln) variant is classified as Uncertain significance - conflicting evidence, for Familial Hypercholesterolemia by applying evidence codes PM2, BP4, BS3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: . PM2: PopMax MAF = 0.0001157 (0.01%) in Latino/Admixed Americans exomes+genomes (gnomAD v2.1.1). . BP4: REVEL = 0.373. it is below 0.50, so splicing evaluation is required. Functional data on splicing not available. A) Variant not on limits. B) Variant does not create GT. Variant is predicted not to alter splicing. . BS3: Level 1 assays: PMID 31106925 Heterologous cells (CHO), FACS assays - result - 100% LDLR expression, binding, and uptake . PP4: Variant meets PM2 and is identified in at least 1 index case with DLCN>=6/ from PMID 31106925, after alternative causes of high cholesterol were excluded.
Color Diagnostics, LLC DBA Color Health	RCV003581734	SCV004358505	uncertain significance	Familial hypercholesterolemia	2023-04-10	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Arg329Gln in the mature protein) replaces arginine with glutamine at codon 350 of the LDLR protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study using transfected CHO cells has shown that this variant does not inhibit LDLR expression and LDL uptake (PMID: 31106925). This variant has been reported in an individual affected with familial hypercholesterolemia (PMID: 31106925). This variant has been identified in 4/250736 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Arg350Pro, is considered to be disease-causing (ClinVar variation ID: 226343), suggesting that arginine at this position is important for LDLR protein function. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
All of Us Research Program, National Institutes of Health	RCV000850045	SCV004842640	uncertain significance	Hypercholesterolemia, familial, 1	2024-09-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV003581734	SCV005830099	uncertain significance	Familial hypercholesterolemia	2024-06-11	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 350 of the LDLR protein (p.Arg350Gln). This variant is present in population databases (no rsID available, gnomAD 0.01%). This missense change has been observed in individual(s) with hypercholesterolemia (PMID: 31106925). ClinVar contains an entry for this variant (Variation ID: 689349). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change does not substantially affect LDLR function (PMID: 31106925). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Department of Genetics of Metabolic Diseases, Institute of Medical & Molecular Genetics, Hospital Universitario Hospital La Paz	RCV000850045	SCV000992184	pathogenic	Hypercholesterolemia, familial, 1	2019-01-01	no assertion criteria provided	clinical testing